The present invention relates to xcex2-alanine derivatives and their use as receptor antagonists. More particularly, it relates to 2-acylamino-xcex2-alanine derivatives and a pharmaceutically acceptable salt thereof and their use as fibrinogen receptor antagonists.
European Patent Application No. 512,831 A1 discloses fibrinogen receptor antagonists. European Patent Application No. 445,796 A2 discloses inhibitors of blood platelets aggregation. International Patent Publication Nos. WO95/08536, WO96/29309 and WO97/33869 disclose N-(3-piperidylcarbonyl)-xcex2-alanine derivatives as platelet-activating factor (PAF) antagonists.
The present invention relates to xcex2-alanine derivatives and their use as fibrinogen receptor antagonists.
The xcex2-alanine derivatives of the present invention can be represented by the following formula (I): 
wherein
R1 is hydrogen atom or an amino protective group;
A is a lower allylene group or a lower alkenylene group;
R2 is hydrogen atom or an amino group which may be substituted with an acyl group selected from the group consisting of
a lower alkanoyl group which may be substituted with amino, lower alkanoylamino, ar(lower)alkoxycarbonylamino, aryl, aroylamino, carboxy, lower alkoxycarbonylamino, ar(lower)alkoxy, lower alkoxycarbonyl, lower alkanoyloxy, lower alkoxy or hydroxy group, among which the aryl and aroylamino may further be substituted with carboxy, lower alkoxy or lower alkoxycarbonyl,
a lower alkoxycarbonyl group which may be substituted with lower alkoxy, aryl or cyclo(lower)alkyl,
a lower alkenyloxylcarbonyl group,
a di(lower)alkylaminosulfonyl group,
a cycloalkanoyl group which may be substituted with lower alkoxy,
an aroyl group which may be substituted with (C3-C6) alkoxy, carbamoyl(lower)alkoxy, N-(lower)alkylcarbamoyl(lower)alkoxy, N,N-di(lower))alkylcarbamoyl(lower)alkoxy, lower alkoxycarbonyl, nitro, cyano, carboxy, carboxy(lower)alkoxy, ar(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, cyclo(lower)alkoxy, lower alkoxycarbonylamino, cyclo(lower)alkyl(lower)alkoxy, lower alkanoylamino or lower alkylcarbamoyl,
an aryloxycarbonyl group,
a heterocyclylcarbonyl group,
a protected carboxycarbonyl group and
a heterocyclyloxycarbonyl group;
R3 is hydrogen atom or an aryl or aralkyl group which may be substituted with one or more of hydroxy and/or lower alkoxy; a moiety represented by the formula: 
xe2x80x83is a bivalent N-containing 6- to 8-membered heterocyclic group;
provided that
(1) when R2 is hydrogen atom, then the moiety of 
xe2x80x83is a bivalent N-containing 7- or 8-membered heterocyclic group and A, R1 and R3 are as defined above, or R3 is hydroxy- or isobutoxy-substituted phenyl group and A, R1 and the moiety of 
xe2x80x83are as defined above,
(2) when R2 is unsubstituted amino group, then the amino protective group for R1 is a lower alkoxycarbonyl group and A, R3 and the moiety of 
xe2x80x83are as defined above, or A is a lower alkenylene group and R1, R3 and the moiety of 
xe2x80x83are as defined above,
(3) when R2 is amino group substituted with an actyl group, then the moiety of 
xe2x80x83is a bivalent N-containing 7-membered heterocyclic group and A, R1 and R3 are as defined above, and
(4) when R2 is an amino group substituted with a cycloalkanoyl group which may be substituted with lower alkoxy, then R1 is hydrogen atom and A, R3 and the moiety of 
xe2x80x83are as defined above.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail in the following.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having 1 to 7 carbon atom(s), unless otherwise indicated.
Suitable lower alkyl moieties in the terms of the lower alkanoyl, lower alkanoylamino, ar(lower)alkoxycarbonylamino, lower alkoxycarbonylanino, ar(lower)alkoxy, lower alkoxycarbonyl, lower alkanoyloxy, lower alkoxy, di(lower)alkylaminosulfonyl, carbamoyl(lower)alkoxy, N-(lower)alkylcarbamoyl(lower)alkoxy, N,N-di(lower)alkylcarbamoyl(lower)alkoxy, carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkoxy and lower alkylcarbamoyl groups may be straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or the like, more suitably the ones having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Suitable examples of the lower alkenyl moieties in the term of lower alkenyloxylcarbonyl groups include straight or branched ones having 2 to 6 carbon atoms, such as vinyl, propenyl (i.e., allyl or 1-propenyl), butenyl, isobutenyl, pentenyl or hexenyl.
Suitable cycloalkyl moieties in the term of cyclo(lower)alkyl, cycloalkanoyl, cyclo(lower)alkoxy and cyclo(lower)alkyl(lower)alkoxy groups include the ones having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Suitable aryl groups and aryl moieties in the terms of the ar(lower)alkoxycarbonylamino, aroylamino, aroyl, ar(lower)alkoxy, aryloxycarbonyl and aralkyl groups may be aromatic hydrocarbon residues having 6 to 12 carbon atoms. Suitable examples are phenyl and naphthyl.
Suitable heterocyclic groups in the term of the heterocyclylcarbonyl and heterocyclyloxycarbonyl groups may include mono- or poly-cyclic groups containing at least one hetero atom selected from nitrogen, sulfur and oxygen atoms, such as
(1) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl or 2H-1,2,3-triazolyl], tetrazolyl [e.g., 1H-tetrazolyl or 2H-tetrazolyl] or the like.;
(2) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing an oxygen atom, for example, furyl, pyranyl or the like;
(3) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms, for example, thienyl, thiopyranyl or the like;
(4) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl] or the like;
(5) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl] or the like;
(6) unsaturated condensed heterocyclic groups containing 1 to 2 nitrogen atoms, for example, indolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzimidazolyl or the like;
(7) unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms, for example, benzofuryl, benzopyranyl or the like;
(8) unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms, for example, benzo[b]thienyl or the like;
(9) unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, phenoxazinyl or the like;
(10) unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzoisothiazolyl, phenothiazinyl or the like.
Suitable amino protective groups may include conventional amino protecting groups such as lower alkanoyls (e.g., acetyl or propionyl) and aroyls (e.g., benzoyl or naphthoyl) as explained below, ar(lower)alkyls which may have 1 to 3 suitable substituents (e.g., benzyl, 4-nitorobenzyl, phenethyl, 1-phenethyl, benzhydryl or trityl), lower alkoxy carbonyls (e.g., tert-butoxycarbonyl), ar(lower)alkoxy carbonyls (e.g., benzyloxycarbonyl or fluorenylmethoxycarbonyl).
Suitable carboxy protective groups in the term of protected carboxycarbonyl group may include conventional ones such as lower alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or 1-cyclopropylethyl), halo(lower)allyl groups (e.g., 2-iodomethyl or 2,2,2-trichloroethyl), ar(lower)alxyl groups (e.g., benzyl, trityl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl or 4-hydroxy-3,5-di-tert-butylbenzyl), aryl groups (e.g., phenyl, naphthyl, tolyl or xylyl). Among the above, more suitable ones are lower alkyl groups such as methyl, ethyl or tert-butyl and ar(lower)alkyl groups such as benzyl.
Suitable examples of each group are illustrated in the following in more detail.
Suitable lower alkylene groups may include straight or branched ones having 1 to 6 carbon atoms, such as methylene, methylmethylene, ethylene, methylethylene, trimethylene, tetramethylene, 2-methyltrimethylene, pentamethylene, hexamethylene and the like, more suitably the ones having 1 to 3 carbon atoms such as methylene, ethylene and trimethylene.
Suitable lower alkenylene groups may include straight or branched ones having 2 to 6 carbon atoms, such as vinylene, propenylene, butenylene, pentenylene, hexenylene and the like.
Suitable lower alkanoyl groups may include formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl, isovaleryl, n-heptanoyl, oxalyl, succinyl and pivaloyl.
Suitable lower alkanoylamino groups may include formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, 4-methypentanoylamino, isopentanoylamino, n-heptanoylaznino, oxalylamino, succinylamino and pivaloylamino.
Suitable ar(lower)alkoxycarbonylamino groups may include phenyl(C1-C6)alkoxycarbonylamino (e.g., benzyloxycarbonylamino or phenethyloxycarbonylamino) and naphthyl(C1-C6)alkoxycarbonylamino (e.g., naphthylmethoxycarbonylamino or naphthylethoxycarbonylamino).
Suitable lower alkoxy groups may include methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, secbutoxy and tert-butoxy.
Suitable lower alkoxycarbonyl groups may include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, i-propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, i-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, heptyloxycarbonyl and hexyloxycarbonyl.
Suitable aroylamino groups may include benzoylamino and naphthoylamino.
Suitable lower alkoxycarbonylamino groups may include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, isopropoxycarbonylamino, isobutoxycarbonylamino, sec-butoxycarbonylamino and tert-butoxycarbonylamino.
Suitable ar(lower)alkoxy groups may include benzyloxy, phenethyloxy, phenylpropoxy, phenylbutoxy, phenyl-iso-propoxy, phenyl-iso-butoxy, phenyl-sec-butoxy and phenyl-tert-butoxy.
Suitable lower alkanoyloxy groups may include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, n-heptanoyloxy, oxalyloxy, succinyloxy and pivaloyloxy.
Suitable cyclo(lower)alkyl groups may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Suitable lower alkenyloxylcarbonyl groups may include vinyloxycarbonyl, allyloxycarbonyl and the like.
Suitable di(lower)alkylaminosulfonyl groups may include dimethylaminosulfonyl and diethylaminosulfonyl.
Suitable cycloalkanoyl groups may include cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl and cyclohexanecarbonyl.
Suitable aroyl groups may include benzoyl and naphthoyl.
Suitable carbamoyl(lower)alkoxy groups may include carbamoylmethoxy, carbamoylethoxy, carbamoylpropoxy, carbamoylbutoxy, carbamoylpentyloxy adn carbamoylhexyloxy.
Suitable N-(lower)alkylcarbamoyl(lower)alkoxy groups may include N-methylcarbamoylmethoxy, N-ethylcarbamoylmethoxy, N-methylcarbamoylpropoxy, N-methylcarbamoylbutoxy, N-methylcarbamoylpentyloxy, N-methylcarbamoylhexyloxy and N-hexylcarbamoylmethoxy.
Suitable N,N-di(lower)alkylcarbamoyl(lower)alkoxy groups may include N,N-dimethylcarbamoylmethoxy, N,N-diethylcarbamoylmethoxy, N,N-dipropylcarbamoylmethoxy, N,N-di-iso-propylcarbamoylmethoxy and N,N-dibutylcarbamoylmethoxy.
Suitable carboxy(lower)alkoxy groups may include carboxypropoxy, carboxybutoxy, carboxypentyloxy, carboxyhexyloxy and carboxyheptyloxy.
Suitable lower alkoxycarbonyl(lower)alkoxy groups may include methoxycarbonylmethoxy, ethoxycarbonylmethoxy, propoxycarbonylmethoxy, butoxycarbonylmethoxy, isopropoxycarbonylmethoxy, isobutoxycarbonylmethoxy, sec-butoxycarbonylmethoxy tert-butoxycarbonylmethoxy and methoxycarbonylethoxy.
Suitable cyclo(lower)alkoxy groups may include cyclopropoxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy.
Suitable cyclo(lower)alkyl(lower)alkoxy groups may include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclohexylethoxy.
Suitable lower alkylcarbamoyl groups may include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl and hexylcarbamoyl.
Suitable aryloxycarbonyl groups may include phenoxycarbonyl, naphthoxycarbonyl, tolyloxycarbonyl and mesityloxycarbonyl.
Suitable heterocyclylcarbonyl groups may include nicotinoyl, thenoyl, furoyl and isoxazolylcarbonyl.
Suitable protected carboxycarbonyl groups may include methoxyoxalyl and ethoxyoxalyl.
Suitable heterocyclicoxycarbonyl groups may include furyloxycarbonyl, thienoyloxycarbonyl, isoxazolyloxycarbonyl, 1,2,3-thiadiazolyloxycarbonyl, pyrrolyloxycarbonyl and pyridyloxycarbonyl.
Suitable bivalent N-containing 6- to 8-membered heterocyclic groups may include piperidine-1,3-diyl, 1H-2,3,4,5,6,7-hexahydroazepin-1,3-diyl, 1H-2,5,6,7-tetrahydroazepin-1,3-diyl, 1,2,3,4,5,6,7,8-octahydroazocin-1,3-diyl, 1,2,3,6,7,8-hexahydroazocin-1,3-diyl and the like.
Specific examples of each group having substituent(s) are further illustrated in the following.
The lower alkanoyl groups substituted with amino may be 2-aminoacetyl, 3-aminopropionyl, 4-aminobutyryl, 6-aminohexanoyl, 2-amino-2-methylpropionyl and 2-propionylacetyl.
The lower alkanoyl groups substituted with lower alkanoylamino may be 2-acetylaminoacetyl, 3-acetylaminopropionyl, 4-acetylaminobutyryl and 2-propionylacetyl.
The lower alkanoyl groups substituted with ar(lower)alkoxycarbonylamino may be 2-(benzyloxycarbonylamino)-acetyl and 3-(benzyloxycarbonylamino)propionyl.
The lower alkanoyl groups substituted with aryl which may further be substituted with carboxy, lower alkoxy or lower alkoxycarbonyl may be 4-carboxyphenylacetyl, 4-methoxyphenylacetyl, 4-methoxyphenylpropionyl and 4-methoxycarbonylphenylacetyl.
The lower alkanoyl groups substituted with aroylamino which may further be substituted with carboxy, lower alkoxy or lower alkoxycarbonyl may be 2-((4-carboxybenzoyl)amino)acetyl, 2-((4-methoxycarbonybenzoyl)amino)acetyl, 3-((4-carboxybenzoyl)-amino)propionyl and 3-((4-methoxycarbonylbenzoyl)amino)-propionyl.
The lower alkanoyl groups substituted with carboxy may be carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxy-iso-butyryl and carboxy-n-heptanoyl.
The lower alkanoyl groups substituted with lower alkoxycarbonylamino may be methoxycarbonylaminoacetyl, ethoxycarbonylaminoacetyl, isobutoxycarbonylaminoacetyl, isobutoxycarbonylaminopropionyl, propoxycarbonylaminoacetyl and butoxycarbonylaminopropionyl.
The lower alkanoyl groups substituted with ar(lower)alkoxy may be benzyloxyacetyl, benzyloxypropionyl, naphthylmethoxyacetyl and naphthylmethoxypropionyl.
The lower alkanoyl groups substituted with lower alkoxycarbonyl may be methoxycarbonylacetyl, methoxycarbonylpropionyl, ethoxycarbonylacetyl and propoxycarbonylpropionyl.
The lower alkanoyl groups substituted with lower alkanoyloxy may be acetyloxyacetyl, acetyloxypropionyl, propionyloxyacetyl and propionyloxypropionyl.
The lower alkanoyl groups substituted with lower alkoxy may be methoxyacetyl, methoxypropionyl,ethoxyacetyl and ethoxypropionyl.
The lower alkanoyl group substituted with hydroxy may be hydroxyacetyl, hydroxypropionyl, hydroxybutyryl and hydroxyhexanoyl.
The lower alkoxycarbonyl groups substituted with lower alkoxy may be methoxymethoxycarbonyl and 2-methoxyethoxycarbonyl.
The lower alkoxycarbonyl groups substituted with aryl may be benzyloxycarbonyl and phenethyloxycarbonyl.
The lower alkoxycarbonyl groups substituted with cyclo(lower)alkyl may be cyclopropylmethoxycarbonyl, cyclobutylmethoxycarbonyl, cyclopentylmethoxycarbonyl, cyclohexylmethoxycarbonyl, cyclopropylethoxycarbonyl, cyclobutylethoxycarbonyl, cyclopentylethoxycarbonyl and cyclohexylethoxycarbonyl.
The cycloalkanoyl groups substituted with lower alkoxy may be methoxycyclopropylcarbonyl, methoxycyclobutylcarbonyl, methoxycyclopentylcarbonyl and methoxycyclohexylcarbonyl.
The aroyl groups substituted with C3-C6 alkoxy may be 4-propoxybenzoyl, 4-isopropoxybenzoyl, 4-isobutoxybenzoyl, isopentyloxybenzoyl, isohexyloxybenzoyl and neopentyloxybenzoyl.
The aroyl groups substituted with carbamoyl(lower)alkoxy may be 4-carbamoylmethoxybenzoyl and 4-carbamoylethyloxybenzoyl.
The aroyl groups substituted with N-(lower)alkyl-carbamoyl(lower)alkoxy may be 4-(N-methylcarbamoylmethoxy)benzoyl, 4-(N-ethylcarbamoylmethoxy)benzoyl, 4-(N-isopropylcarbamoylmethoxy)benzoyl, 4-(N-n-butylcarbamoylmethoxy)benzoyl, 3-(isobutylcarbamoylmaethoxy)benzoyl and 4-(isobutylcarbamoylmethoxy)benzoyl.
The aroyl groups substituted with N,N-di(lower)alkylcarbamoyl(lower)alkoxy may be 4-(N,N-dimethylcarbamoylmethoxy)benzoyl, 4-(N,N-diethylcarbamoylmethoxy)benzoyl, 4-(N,N-dipropylcarbamoylmethoxy)benzoyl, 4-(N,N-di-iso-propylcarbamoylmethoxy)benzoyl and 4-(N,N-dibutylcarbamoylmethoxy)benzoyl.
The aroyl groups substituted with lower alkoxycarbonyl may be methoxycarbonylbenzoyl, ethoxycarbonylbenzoyl, propoxycarbonylbenzoyl, iso-propoxycarbonylbenzoyl, butoxycarbonylbenzoyl, tert-butoxycarbonylbenzoyl and methoxycarbonylnaphthoyl.
The aroyl groups substituted with nitro may be nitrobenzoyl and nitronaphthoyl.
The aroyl groups substituted with cyano may be cycanobenzoyl and cycanonaphthoyl.
The aroyl groups substituted with carboxy may be carboxybenzoyl and carboxynaphthoyl.
The aroyl groups substituted with carboxy(lower)alkoxy may be carboxypropoxybenzoyl, carboxybutoxybenzoyl, carboxypentoxybenzoyl and carboxyhexyloxybenzoyl.
The aroyl groups substituted with ar(lower)alkoxy may be benzyloxybenzoyl, phenethyloxybenzoyl, phenylpropoxybenzoyl, phenylbutoxybenzoyl and phenylisopropoxybenzoyl.
The aroyl groups substituted with lower alkoxycarbonyl(lower)alkoxy may be methoxycarbonylmethoxybenzoyl, ethoxycarbonylmethoxybenzoyl, propoxycarbonylmethoxybenzoyl and butoxycarbonylmethoxybenzoyl.
The aroyl groups substituted with cyclo(lower)alkoxy may be cyclopropoxybenzoyl, cyclobutoxybenzoyl and cyclopentoxybenzoyl.
The aroyl groups substituted with lower alkoxycarbonyl-amino may be methoxycarbonylaminobenzyol and ethoxycarbonylaminobenzoyl.
The aroyl groups substituted with cyclo(lower)alkyl(lower)-alkoxy may be cyclopropylmethoxybenzoyl, cyclobutylmethoxybenzoyl and cyclopentylmethoxybenzoyl.
The aroyl groups substituted with lower alkanoylamino may be formylaminobenzoyl, acetylaminobenzoyl, propionylaminobenzoyl and butyrylaminobenzoyl.
The aroyl groups substituted with lower alkylcarbamoyl may be methylcarbamoylbenzoyl, ethylcarbamoylbenzoyl and propylcarbamoylbenzoyl.
The aryl groups substituted with hydroxy may be 3-hydroxyphenyl, 4-hydroxyphenyl and 3,4-dihydroxyphenyl.
The aryl groups substituted with lower alkoxy may be 2-methoxyphenyl, 3-methoxyohenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-(2,2-dimethyl)propoxyphenyl, 3-isobutoxyphenyl, 4-isobutoxyphenyl and 4-(2-methyl)pentoxyphenyl.
The aralkyl groups substituted with hydroxy may be 4-hydroxybenzyl, 3,4-dihydroxybenzyl and 4-hydrozyphenethyl.
The aralkyl groups substituted with lower alkoxy may be 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-methoxyphenethyl and 3,4-dimethoxyphenethyl.
Preferred embodiment of the object compounds are derivatives of the formula (I), wherein R1 is hydrogen, A is a lower alkylene group, R2 is an amino group which is substituted with an aroyl group substituted with lower alkylcarbamoyl, R3 is hydrogen atom and the moiety represented by the formula: 
is piperidine-1,3-diyl.
More preferred embodiment of the object compounds are derivatives of the formula (I), wherein R1 is hydrogen, A is ethylene group, R2 is an amino group which is substituted with a benzoyl group substituted with lower alkylcarbamoyl, R3 is hydrogen atom and the moiety represented by the formula: 
is piperidine-1,3-diyl.
Suitable salts of the compounds (I) are conventional non-toxic pharmaceutically acceptable salts and may be salts with inorganic bases, for example, an alkali metal (e.g. sodium or potassium), an alkaline earth metal (e.g. calcium or magnesium), ammonium; a salt with an organic base, for example, an organic amine (e.g. triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, or N,Nxe2x80x2-dibenzylethylenediamine); an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate or phosphate); an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate or p-toluenesulfonate); a salt with a basic or acidic amino acid (e.g. arginine, aspartate or glutamate); and the like, and preferable examples thereof are the acid addition salts.
The compounds (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers.
The compounds (I) may also exist in tautomeric forms, and accordingly the present invention includes both of mixtures and separated individual tautomers.
It is further to be noted that isomerization or rearrangement of the compounds (I) may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention.
The compounds (I) and their salts can be in a form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
Also included in the scope of the invention are radiolabelled derivatives of the compounds (I) which are suitable for biological studies.
An compound (I) or a salt thereof can be prepared by the following processes. 
wherein R1, R2, R3 and A are each as defined above,
R4 is hydrogen atom or a carboxy protective group,
R5 is an acyl group as defined above, the moiety of 
xe2x80x83is a bivalent N-containing 6- to 8-membered heterocyclic group containing one double bond and
the moiety of 
xe2x80x83is a bivalent N-containing 6- to 8-membered saturated heterocyclic group.
The processes for preparing the object compound (I) of the present invention are explained in detail in the following.
Process 1
The compound (Ia) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the carboxy group or a salt thereof with the compound (III) or its reactive derivative at the piperidine NH group or a salt thereof.
Suitable reactive derivative at the carboxy group of the compound (II) may include an acid halide, an acid anhydride, an activated amide, an activated ester and the like. Examples of the suitable reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid], dialkylphospohrous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g., methanesulfonic acid], aliphatic carboxylic acid [e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid] or aromatic carboxylic acid [e.g., benzoic acid]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester [e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N+xe2x95x90Cxe2x80x94] ester, vinyl ester, propargyl ester, p-nitorophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitorophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester or 8-quinolyl thioester], or an ester with a N-hydroxy compound [e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy-1H-benzotriazole] and the like. A reactive derivative can be optionally selected from the above according to the kind of the compound (II) to be used.
Suitable salts of the compound (II) or its reactive derivative can be referred to those as exemplified for the compound (I).
Suitable reactive derivative at the piperidine NH group of the compound (III) may include Shiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (III) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by the reaction of the compound (III) with phosphorus trichloride or phosgene, and the like.
Suitable salts of the compound (III) or its reactive derivative can be referred to those as exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol or ethanol], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which dose not adversely affect the reaction. These conventional solvents may also be used in a mixture with water.
In this reaction, when the compound (II) is used in a free acid form or its salt form, the reaction is preferable carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexyl-carbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diethylcarbodiimide, N,Nxe2x80x2-diisopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,Nxe2x80x2-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkylphosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g., ethyl chloroformate or isopropyl chloroformate]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzensulfonyloxy)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorous oxychloride, methanesulfonyl chloride, etc; or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower))alkylbenzylamine or the like.
The reaction is usually carried out under cooling to warming, although the reaction temperature is not critical.
Process 2
The compound (Ia) or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivative at the carboxy group or a salt thereof with the compound (V) or its reactive derivative at the amino group or a salt thereof.
The reaction can be carried out in a similar manner to that of Process 1 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g., reactive derivative, solvent or reaction temperature] of this reaction are to be referred to those as explained in the above Process 1.
Process 3
The compound (Ia) or a salt thereof can be prepared by reacting the compound (Ib) or its reactive derivative at the amino group or a salt thereof with the compound (VI) or its reactive derivative at the carboxy group or a salt thereof.
This reaction is carried out according to a conventional manner such as the ones described in the above Process 1 or similar manners thereto.
Process 4
The compound (Id) or a salt thereof can be prepared by subjecting a compound (Ic) or a salt thereof to reduction, i.e., chemical reduction or catalytic reduction.
Suitable reducing agents to be used in chemical reduction may be a combination of metal [e.g., tin, zinc or iron] or metallic compound [e.g., chromium chloride or chromium acetate] and an organic or inorganic acid [e.g.; formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid or hydrobromic acid].
Suitable catalysts to be used in catalytic reduction may be conventional ones such as a platinum catalyst [e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide or platinum wire], a palladium catalyst [e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on black, palladium on sulfate or palladium on barium carbonate], a nickel catalyst [e.g., reduced nickel, nickel oxide or Raney nickel], a cobalt catalyst [e.g., reduced cobalt or Raney cobalt], an iron catalyst [e.g., reduced iron or Raney iron], a copper catalyst [e.g., reduced copper, Raney copper or Ullman copper] and the like.
A suitable solvent to be used in the chemical reduction may be a conventional solvent which does not adversely affect the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide or a mixture thereof.
Further, a suitable solvent to be used in the catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran or a mixture thereof.
The reaction is usually carried out under cooling to warming, although the reaction temperature is not critical.
If desired, the amino protective group of R1 and/or carboxy protective group of R2 and/or R4 may be removed by a conventional manner known in the art. The removal of each protective group can be conducted separately or all at once.
The removal methods of the protective group can be selected in accordance with the kinds of the protective groups and the typical methods are hydrolysis with an acid or base or reduction such as catalytic reduction and chemical reduction.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g., sodium or potassium], an alkaline earth metal (e.g., calcium or magnesium), an alkali metal hydroxide [e.g., sodium hydroxide or potassium hydroxide], an alkali metal hydrogen carbonate [(e.g., sodium hydrogencarbonate or potassium hydrogen carbonate], an alkali metal carbonate [e.g., sodium carbonate], an alkali earth metal carbonate [e.g., calcium carbonate], triallylamine [e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine or dibenzylethylenediamine], picoline, 1,5-dizazbicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene or the like.
Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid or trifluoroacetic acid] and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride or hydrogen bromide].
The removal reaction of the protective group using Lewis acid such as trihaloacetic acid [e.g., trichloroacetic acid or trifluoroacetic acid] or the like is preferably carried out in the presence of a cation trapping agent [e.g., anisole or phenol].
The removal reaction is usually carried out in a solvent such as water, an alcohol [e.g., methanol or ethanol], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely affect the reaction. A liquid base or acid can be also used as a solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reduction method applicable for the removal reaction may include chemical reduction and catalytic reduction as described above.
The compounds (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography or the like.
A pharmaceutically acceptable salt of the compound (I) can be prepared by treating a compound (I) with an appropriate base or acid in accordance with the conventional method.
The compounds (I) and salts thereof may be solvates (e.g., hydrate or ethanolate) or inclusion compounds which can be prepared by using a conventional host compound such as xcex2-cyclodextrin.
The starting compounds (II), (III), (IV), (V) and (VI) can be obtained by purchasing commercial products or preparing them according to the methods disclosed is WO96/29309 or the method described in the following Examples or similar method thereto.
In order to exhibit the utility of the compound (I) of the present invention, their activities are shown in the following.
Test: Effect on Platelet Aggregation Induced by Adenosine Diphosphate (ADP)
Test Compound
The Compound of Example 25
Test Method
Platelet rich plasma (PRP) which contains 3xc3x97108 platelets/ml was prepared from human blood. To the 225 xcexcl of PRP, 25 xcexcl of the solution of the test compound in water was added, and then stirred for 2 minutes at 37xc2x0 C. To the solution 5 xcexcl of ADP (final 2.5 xcexcM) was added as an aggregation inducer. Aggregation was measured by using an aggregometor (NBS HEMA-TRACER 801). Activity of inducer (test compound) was expressed as IC50 value, i.e., dose required for complete inhibition of platelet aggregation.
As shown in the above table 1, the compound (I) of the present invention has inhibitory activity against platelet aggregation.
As shown in the above, the compounds (I) of the present invention may exhibit pharmacological activities as a fibrinogen receptor antagonist. Therefore, the compounds (I) of the invention are useful as a glycoprotein IIb/IIIa antagonist and an inhibitor of platelet aggregation, especially as:
a drug for prevention and/or treatment of diseases caused by thrombus formation such as arterial thrombosis, arterial sclerosis, ischemic heart diseases [e.g., angina pectoris (e.g., stable angina pectoris or unstable angina pectoris including imminent infraction), myocardial infarction (e.g., acute myocardial infarction) or coronary thrombosis], ischemic brain diseases [e.g., cerebral infarction {e.g., cerebral thrombosis (e.g., acute cerebral thrombosis) or cerebral embolism}, transient cerebral ischemia (e.g., transient ischemic attack) or cerebrovascular spasm after cerebral hemorrhage (e.g., cerebrovascular spasm after subarachnoid hemorrhage)], pulmonary vascular diseases (e.g., pulmonary thrombosis or pulmonary embolism), peripheral circulatory disorder [e.g., arteriosclerosis obliterans, thromboangiitis obliterans (i.e., B{overscore (u)}rger""s disease), Raynaud""s disease, complication of diabetes mellitus (e.g., diabetic angiopathy or diabetic neuropathy) or phlebothrombosis (e.g., deep vein thrombosis)],
a drug for prevention and/or treatment of diseases such as conjunctive diseases [e.g., conjunctivitis (e.g., allergic conjunctivitis, vernal conjunctiviti, keratoconjunctivitis sicca, viral conjunctivitis and bactterial conjunctivitis)], uveal diseases [e.g., unveitis (e.g., Behcet disease, harada disease, sympathetic opthalmia, sarcoidosis and diabetic iritis)], scieral diseases [e.g., scleritis], corneal deseases [e.g., corneal neocascularization, keratitis, corneal edema, corneal opacity, corneal dystrophy, keratoconus and neuroparalytic keratitis], retinal or vitreous diseases [e.g., diabetic retinopathy, retinal artery occlusion, retinal vein occlusion, central setous chorioretinopathy, central hemorrhagic chorioretinitis, macular degeneration, retinal detachment, retinal pigmentary degeneration, macular neovascularization, macular hole, proliferative vitreoretinopathy, vitreous hemorrhage and vitreous opacity], lens disease [e.g., cataract (e.g., senile cataract, traumatic cataract, diabetic cataract and atopic cataract)], glaucoma [e.g., primary open-angle glaucoma, primary angle-closure galucoma, normal tension glaucoma and neovascular galucoma], ocular hypertension, vision disorders [e.g., amblyopia, color vision defect and night blindeness], referactive errors [e.g., astigmatism, hyperopia, myopia and presbyopia], lacrimal apparatus diseases [e.g., dry eye syndromes, lacrimal duct obstraction and dacryocystitis] or the like;
a drug for prevention and/or treatment of restenosis and/or reocclusion such as restenosis and/or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), restenosis and/or recclusion after the administration of thrombolytic drug (e.g., tissue plasminogen activator (TPA)) or the like;
a drug for adjuvant therapy with thrombolytic drug (e.g., TPA) or anticoagulant (e.g., heparin);
a drug for prevention and/or treatment of the thrombus formation in case of vascular surgery, valve replacement, extracorporeal circulation [e.g., surgery (e.g., open heart surgery or pump-oxygenator) or hemodialysis], transplantation or the like;
a drug for prevention and/or treatment of disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g., nephritis), immune diseases or the like;
a drug for inhibiting metastasis; or the like.
The present invention also provides a pharmaceutical composition which comprises, as an active ingredient, a compound (I) of the present invention or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention can be used for prevention and/or treatment of a disease caused by thrombus formation; restenosis or reocclusion; thrombus formation in the case of vascular surgery, valve replacement, extracorporeal circulation or transplantation; disseminated intravascular coagulation; thrombotic thrombocytopenic; essential thrombocytosis; inflammation; immune disease; or metastasis;
or for adjuvant therapy with a thrombolytic drug or anticoagulant.
The pharmaceutical composition of the present invention may be in solid, semisolid or liquid form, which contains a compound (I), as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation. Examples of organic or inorganic carrier or excipient are the usual non-toxic, pharmaceutically acceptable ones for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
The pharmaceutical composition of the present invention can be manufactured by a conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavailability of a drug can be applied to the pharmaceutical composition of the present invention.
For applying the composition to a human being or an animal, it is preferable to apply it by intravenous (including i.v. infusion), intramuscular, pulmonary, or oral administration, or insufflation including aerosols from metered dose inhalator, nebulizer or drug powder inhalator.
While the dosage of therapeutically effective amount of the compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.001-10 mg of the compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.001-100 mg of the compound(I) per kg weight of a human being or an animal, in case of oral administration, a daily dose of 0.001-200 mg of the compound(I) per kg weight of a human being or an animal in generally given for the prevention and/or treatment of aforementioned diseases in a human being or an animal.
The pharmaceutical composition comprises the derivative (I) in an amount sufficient to produce the desired effect upon the process or condition of the diseases.
According to the present invention, the compound (I) of the invention or pharmaceutically acceptable salt thereof can be used as a medicament for the manufacture of a medicament having an activity of fibrinogen receptor antagonist.
The present invention further provide a method for prevention of a disease caused by thrombus formation; restenosis or reocclusion; thrombus formation in the case of vascular surgery, valve replacement, extracorporeal circulation or transplantation; disseminated intravascular coagulation; thrombotic thrombocytopenic; essential thrombocytosis; inflammation; immune disease; or metastasis; which comprises administering the derivative of the formula (I) or a pharmaceutically acceptable salt thereof to a human being or an animal.
The present invention still further provide a method for treatment of a disease caused by thrombus formation; restenosis or reocclusion; thrombus formation in the case of vascular surgery, valve replacement, extracorporeal circulation or transplantation; disseminated intravascular coagulation; thrombotic thrombocytopenic; essential thrombocytosis; inflammation; immune disease; or metastasis; which comprises administering the derivative of the formula (I) or a pharmaceutically acceptable salt thereof to a human being or an animal suffering any of the above disease.
The present still further provide a method for adjuvant therapy with a thrombolytic drug or anticoagulant; which comprises administering the derivative of the formula (I) or a pharmaceutically acceptable salt thereof to a human being or an animal suffering a disease to be treated with the thrombolytic drug or anticoagulant.
The following Examples are given for illustrating the present invention in more detail, but it is to be noted that the scope of the present invention is not limited by these Examples.